DESCRIPTION(adapted from applicant's abstract): Neuronal activity in the cerebral cortex underlies sensory processing, learning and memory, sleep, and the generation of epileptic seizures. These tasks are diverse, yet depend upon the operation of the same local and global neuronal networks in the neocortex. Investigations of the neurophysiological basis for these different properties of cortical function have recently begun to merge together into a unified understanding of the operation of local and long-range cortical networks. Our advance in knowledge of cortical function, however, is limited in part by the ability to directly address the cellular mechanisms of operation of these circuits. In vitro studies have traditionally been limited to the analysis of the properties of single cells and synapses. Circuit activity in the neocortex has been restricted to activity generated in response to artificial electrical stimulation of afferent pathways or the administration of convulsants or epileptic conditions. We have recently discovered an in vitro neocortical slice preparation that spontaneously generates normal network activity. Traditionally, the extracellular solution in slice medium contains abnormally high levels of Ca2+ and Mg2+ in order to foster stability of intracellular recordings. By changing extracellular levels of these ions to match that occurring in vivo, we have obtained slices of neocortex that generate periods of persistent activity of 0.75-1.5 seconds in duration and that recur once every 2-5 seconds. This pattern of activity is nearly identical to that occurring in vivo during periods of slow wave sleep and anesthesia, and underlies the generation of the so-called "slow oscillation." We have recorded this pattern of activity in layers Il-VI of neocortical slices from both occipital and prefrontal cortical areas and found that it associated with a synchronous depolarization of all cortical neurons (pyramidal and non-pyramidal) that is mediated by recurrent network excitation and inhibition. Alteration in the balance of excitation and inhibition result in the generation of epileptiform activity resembling interictal spikes and electrographic seizures. In this application, we propose to examine the precise cellular and network mechanisms by which local cortical networks generate this pattern of recurring persistent activity and how this activity may be modulated by the administration of neuromodulatory transmitters. Specifically, we will address both the mechanisms of generation of the depolarized and hyperpolarized states of activity in cortical neurons, as well as the mechanisms by which the activity propagates throughout the network. We hypothesize that this activity is generated as a natural consequence of recurrent excitation and inhibition and divergent and convergent connections in local cortical networks, interacting with intrinsic membrane properties, particularly those underlying adaptation. By understanding the mechanisms by which local cortical networks generate rhythmic periods of sustained activity, we expect to gain in sight into the mechanisms of EEG generation during sleep, the generation of persistent activity during short term memory formation, the operation of local cortical circuits in sensory processing, and the generation of some forms of epileptic seizures.